Palmoplantar keratoderma-deafness syndrome: genes and variants
Palmoplantar keratoderma-deafness syndrome is linked to 1 analyzed protein (GJB2). 10 DNA variants are known to cause it; 1 more are uncertain, and 0 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Palmoplantar keratoderma-deafness syndrome
GJB2: Gap junction beta-2 protein
Its connexin 26 channels support potassium and metabolite recycling within the cochlea and communication across epithelial gap junctions. Biallelic pathogenic variants are among the most common causes of congenital nonsyndromic hearing loss, while dominant variants can cause syndromic deafness with skin disease.
10 disease-causing and 1 uncertain variants in GJB2 are linked to Palmoplantar keratoderma-deafness syndrome.
Where Palmoplantar keratoderma-deafness syndrome variants cluster
- GJB2 Transmembrane (positions 136–156): 3 of 10 disease-causing changes, 3.2× more than its size predicts.
Known disease-causing variants in Palmoplantar keratoderma-deafness syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| GJB2 R143W | 143 | Transmembrane | Disease-causing (★★★★) |
| GJB2 R32C | 32 | Transmembrane | Disease-causing (★★★★) |
| GJB2 E147K | 147 | Transmembrane | Disease-causing (★★) |
| GJB2 R127C | 127 | Cytoplasmic | Disease-causing (★★) |
| GJB2 G59R | 59 | Extracellular | Disease-causing (★★) |
| GJB2 K122I | 122 | Cytoplasmic | Disease-causing (★★) |
| GJB2 N206S | 206 | Transmembrane | Disease-causing (★★) |
| GJB2 S139N | 139 | Transmembrane | Disease-causing (★★) |
| GJB2 H73R | 73 | Extracellular | Disease-causing |
| GJB2 K22N | 22 | Transmembrane | Disease-causing |
Which prediction tools work for Palmoplantar keratoderma-deafness syndrome
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 89 out of 100
Same protein, different disease
- Autosomal recessive nonsyndromic hearing loss 4 is also caused by GJB2 variants; they fall mostly in different places as the Palmoplantar keratoderma-deafness syndrome variants (38 disease-causing).
- Nonsyndromic genetic hearing loss is also caused by GJB2 variants; they fall partly in the same places as the Palmoplantar keratoderma-deafness syndrome variants (28 disease-causing).
- Rare genetic deafness is also caused by GJB2 variants; they fall mostly in different places as the Palmoplantar keratoderma-deafness syndrome variants (25 disease-causing).
- Mutilating keratoderma is also caused by GJB2 variants; they fall mostly in different places as the Palmoplantar keratoderma-deafness syndrome variants (15 disease-causing).
- Ichthyosis, hystrix-like, with hearing loss is also caused by GJB2 variants; they fall mostly in different places as the Palmoplantar keratoderma-deafness syndrome variants (13 disease-causing).
Diseases related to Palmoplantar keratoderma-deafness syndrome
- Autosomal recessive nonsyndromic hearing loss 4, also linked to GJB2
- Noonan syndrome, also linked to GJB2
- Rare genetic deafness, also linked to GJB2
- Autosomal dominant nonsyndromic hearing loss, also linked to GJB2
- Nonsyndromic genetic hearing loss, also linked to GJB2
- Hearing loss, also linked to GJB2
- Monogenic hearing loss, also linked to GJB2
- Mutilating keratoderma, also linked to GJB2
- Autosomal dominant keratitis-ichthyosis-hearing loss syndrome, also linked to GJB2
- Ichthyosis, hystrix-like, with hearing loss, also linked to GJB2
- Knuckle pads, deafness AND leukonychia syndrome, also linked to GJB2
- Deafness, also linked to GJB2
Frequently asked questions
Which genes are linked to Palmoplantar keratoderma-deafness syndrome?
In CATVariant, Palmoplantar keratoderma-deafness syndrome is linked to 1 analyzed protein: GJB2 (Gap junction beta-2 protein).
How many genetic variants are linked to Palmoplantar keratoderma-deafness syndrome?
33 variants: 10 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1 are of uncertain significance or have conflicting reports.
Which uncertain variants in Palmoplantar keratoderma-deafness syndrome look disease-causing?
None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.
Which variant effect predictor works best for Palmoplantar keratoderma-deafness syndrome?
Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 10 disease-causing and 9 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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